The neurotransmitter serotonin is an important regulator of energy balance. In the brain, serotonergic fibres from midbrain raphe nuclei project to key feeding centres, where serotonin acts on specific receptors to modulate the activity of various downstream neuropeptide systems and autonomic pathways and thus affects ingestive behaviour and energy expenditure. Serotonin, released by intestinal enterochromaffin cells, also appears to regulate energy homeostasis through peripheral mechanisms. Serotonergic effects on energy balance lead to secondary effects on glucose homeostasis, based on a well-established link between obesity and insulin resistance. However, serotonergic pathways may also directly affect glucose homeostasis through regulation of autonomic efferents and/or action on peripheral tissues. Several serotonergic compounds have been evaluated for clinical use in the treatment of obesity and type 2 diabetes; results of these trials are discussed here. Finally, future directions in the elucidation of serotonergic metabolic regulation are discussed.